Method for the manufacture of flat permeable membrane

ABSTRACT

A method of manufacture of flat permeable membrane comprises the steps of mixing a polyolefin, an organic filler uniformly dispersible in the polyolefin in the molten state, and crystal seed forming agent for the polyolefin; discharging the resultant mixture in the molten state through a die; bringing one surface of the discharged molten membrane into contact with a cooling roll; placine the cooled and solidified flat membrane into contact with an extractant capable of dissolving and extracting the organic filler and capable of dissolving the polyolefin; and subjecting the cooled and solidified flat membrane in a fixed state in longitudinal and lateral directions to a heat treatment at a temperature 20° to 50° C. lower than the melting point of the polyolefin.

This is a division of application Ser. No. 796,433, filed Nov. 8, 1985now U.S. Pat. No. 4,743,375.

BACKGROUND OF THE INVENTION

1. Field of the Invention:

This invention relates to a permeable membrane and a method for themanufacture thereof. Particularly, this invention relates to a permeablemembrane useful as for filtration of blood plasma and a method for themanufacture of the permeable membrane. To be more particular, thisinvention relates to a permeable membrane possessed of pores of acontrolled diameter and enabled to provide efficient removal ofpathogenic macromolecules, ensure recovery of albumin in a high ratioand permit efficient treatment of a large amount of blood plasma and toa method for the manufacture of the permeable membrane.

2. Description of Prior Art:

Heretofore, various permeable membranes have been used for theseparation of whole blood into blood corpuscles and blood plasma. Forexample, the permeable membrane for the separation of blood plasma isused for the preparation of a blood plasma medicament for transfusion,for the pretreatment of an artificial kidney, and for the therapyresorting to change of blood plasma. The therapy by the change of bloodplasma has been demonstrated to be effective against suchauto-immunizing diseases as hepatic insufficiency, serious myasthenia,and chronic arthrorheumatism. This therapy is effectively carried out byseparating the whole blood from the patient into blood corpuscles andblood plasma, then discarding the blood plasma containing a pathogenicsubstance, and adding to the blood corpuscles the blood plasma takenfrom a healthy man or a blood plasma medicament. The use of the bloodplasma medicament entails such problems as the difficulty in theprocurement of the medicament itself and the possibility of evil effectof infections factor. Thus, the method which comprises clarifying theblood plasma separated from the patient's own whole blood andrecombining the clarified blood plasma with the blood corpuscles alsoseparated from the whole blood proves desirable. The desirability ofdeveloping a membrane effective for the purpose of this separation isurged.

As membranes useful for such separation of blood plasma as describedabove, regenerated cellulose membrane, cellulose acetate membrane,polyvinyl alcohol membrane, polysulfone membrane, polymethylmethacrylate membrane, etc. have been known to the art. These highmolecular membranes are deficient in mechanical strength, pore diameterof membrane, capacity for treatment of blood plasma, etc. Most of themare impervious to albumin which is beneficial to the human system,pervious not only to albumin but also to pathogenic macromolecules, orsusceptible of early clogging and, therefore, incapable of removingpathogenic macromolecules in a sufficient amount. The term "pathogenicmacromolecule" as used herein means immune globulin M (IgM, Mw about950,000), low density ripoprotein (LDL, Mw about 1,200,000 to3,300,000), immune complexes, rheumatic factor, etc. which have largermolecular weights than albumin. For the purpose of removing pathogenicmacromolecules aimed at and returning albumin as a beneficial bloodplasma component to the patient's system, it is necessary to use aseparation membrane which possesses desired pore diameter and porosityand a membranous texture difficult to clog, and permits clarification ofa large amount of blood plasma.

As a separation membrane for the removal of blood plasma components ofmedium to high molecular weights, there has been proposed a porouspolyethylene hollow-fiber membrane which is made of high-densitypolyethylene having a density of at least 0.955 g/cm³, possessed of amultiplicity of fine pores penetrating the wall thereof from the innerwall surface through the outer wall surface of the hollow fiber,oriented in the direction of length of the hollow fiber, and possessedof a porosity in the range of 30 to 90% by volume (Japanese PatentLaid-open SHO No. 58(1983)-75,555). In the hollow fiber membranedescribed above, since the fine pores are mechanically formed by colddrawing a high-orientation blood plasma type unstretched hollow fiberand subsequently hot drawing the cold drawn hollow fiber and, moreover,the fine pores so formed are substantially straight and substantiallyuniform in diameter from the inner wall surface through the outer wallsurface, the pore density per unit volume cannot be increased and thecapacity for blood plasma treatment per unit surface area is small andthe ratio of recovery of albumin is low. Further, the membrane isreadily fractured by orientation and is heavily deformed and shrunken bythe intense heat as generated during the sterilization with anautoclave, for example.

A hollow fiber made of a vinyl alcohol type polymer and possessed of acompacted layer on at least one of the opposite surfaces of the hollowfiber membrane and a porous layer in the interior of the web of thehollow fiber membrane has been proposed (U.S. Pat. No. 4,402,940). Sincethe hollow fiber membrane of this type is obtained by spinning thesolution of the vinyl alcohol type polymer, however, it suffers from thedisadvantage that the pore density per unit volume cannot be increased,the capacity for blood plasma treatment per unit volume is small, thepathogenic macromolecules cannot be sufficiently removed, and the ratioof recovery of albumin, etc. is low.

There has been proposed a permeable membrane which is produced bypreparing a mixture of a polymer such as crystalline polyolefin orpolyamide which is sparingly soluble in a solvent and is stretchablewith a compound which is partially compatible with the polymer and isreadily soluble in a solvent, molding the mixture in the form of film,sheet, or hollow member, treating the molded mixture with a solvent,drying the wet molded mixture, and stretching the dried molded mixturemonoaxially or biaxially at an elongation of 50 to 1,500% (U.S. Pat. No.4,100,238). Since this membrane is stretched exclusively for the purposeof enlarging the pores in diameter, it exhibits low mechanical strengthand poor durability. Further since the pores are substantially uniformin structure in the opposite surfaces and in the interior and thepolymer crystals are coarse, it separates the components of medium tohigh molecular weights with difficulty despite its low strength.

It is, therefore, an object of this invention to provide a novelpermeable membrane and a method for the manufacture of this permeablemembrane.

Another object of this invention is to provide a permeable membraneuseful as for filtration of crystals and a method for the manufacture ofthe permeable membrane.

Still another object of this invention is to provide a permeablemembrane possessed of pores of a controlled diameter and enabled torecover albumin in a high ratio, remove pathogenic macromolecules withhigh efficiency, and treat a large amount of blood plasma and a methodfor the manufacture of the permeable membrane.

Yet another object of this invention is to provide a porous membraneuseful for separating blood components having good heat stabilitywithout any change in membrane structure and permeability by thermalhistory and a method for the manufacture thereof.

Still yet another object of this invention is to provide a porousmembrane capable of giving sufficient permeability without furtherstretching and a method for the manufacture thereof.

SUMMARY OF THE INVENTION

The objects described above are attained by a flat permeable membranepolyolefin 10 to 500 μm in thickness, which has in one surface thereof acompact layer formed of intimately bound fine polyolefin particlespossessed of fine pores and in the interior and the other surfacethereof a layer formed of an aggregate of fine discrete polyolefinparticles of an average diameter in the range of 0.01 to 5 μm soadjoined as to form the fine labyrinthically continuing through poresand which, therefore, establishes communication between the oppositesurfaces of the membrane.

This invention also relates to a flat permeable membrane wherein thecompact layer accounts for not more than 30% of the total thickness ofthe membrane. This invention relates also to a flat permeable membranewherein the polyolefin membrane has a porosity in the range of 10 to 85%preferably 10 to 60%. This invention relates to a flat permeable porousmembrane wherein the fine pores in the compact layer have an averagediameter in the range of 0.01 to 5 μm. Further this invention relates toa flat permeable membrane wherein the fine discrete particles formingthe layers of an aggregate of particles have an average diameter in therange of 0.02 to 1.0 μm. This invention further relates to a flatpermeable membrane which is made of a polyolefin selected from the groupconsisting of polyethylene, polypropylene, and ethylene-propylenecopolymer. This invention relates further to a flat permeable membranewhich has a porosity in the range of 10 to 85% and a shrinkage of notmore than 6.0% in a heat treatment performed at 121° C. for 120 minutes.This invention relates to a permeable membrane which is a porousmembrane for the separation of blood components. The thickness of themembrane preferably is in the range of 20 to 300 μm. The porositypreferably is in the range of 30 to 80%. The average diameter of saidfine pores preferably is in the range of 0.02 to 2.0 μm. The thermalshrinkage preferably is not more than 3.0%.

The aforementioned objects are further attained by a method for themanufacture of a flat permeable membrane, which is characterized by thesteps of mixing a polyolefin, an organic filler uniformly dispersible inthe polyolefin in the molten state thereof, and a crystal seed formingagent, discharging the resultant mixture in the molten state thereofthrough a die, bringing one surface of the discharged molten membraneinto contact with a cooling roll thereby cooling and solidifying themembrane, and placing the cooled and solidified flat membrane in contactwith an extractant incapable of dissolving the polyolefin therebyextracting and removing the organic filler from the web of the membrane.

The invention relates to a method for the manufacture of a flatpermeable membrane, wherein the organic filler is a hydrocarbon having aboiling point exceeding the melting point of the polyolefin. Further,this invention relates to a method for the manufacture of a flatpermeable membrane, wherein the hydrocarbon is liquid paraffin or anα-olefin oligomer. This invention relates to a method for themanufacture of a flat permeable membrane, wherein the organic filler isincorporated in an amount in the range of 35 to 600 parts by weight,based on 100 parts by weight of the polyolefin. This invention alsorelates to a method for the manufacture of a flat permeable membrane,wherein the polyolefin is at least one member selected from the groupconsisting of polyethylene, polypropylene, and ethylene-propylenecopolymer. This invention relates also to a method for the manufactureof a flat permeable membrane, wherein the crystal seed forming agent isan organic heat-resisting substance having a melting point of not lessthan 150° C. and a gel point exceeding the temperature at which thepolyolefin begins to crystallize. This invention relates to a method forthe manufacture of a flat permeable membrane, wherein the crystal seedforming agent is incorporated in an amount in the range of 0.1 to 5parts by weight, based on 100 parts by weight of the polyolefin.Further, this invention relates to a method for the manufacture of aflat permeable membrane, wherein the extractant is at least one memberselected from the group consisting of alcohols and halogenatedhydrocarbons. This invention relates to a method for the manufacture ofa flat permeable membrane, wherein the temperature of the cooling rollis in the range of 10° to 100° C. This invention relates also to amethod for the manufacture of a flat permeable membrane, which furthercomprises the steps of cooling and solidifying the membrane, maintainingsaid flat membrane in a certain or desired area, and subjecting theformed polyolefin membrane, to a treatment at a temperature 20° to 50°C. lower than the melting point of the polyolefin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a model cross section of a flat permeable membrane embodyingthis invention,

FIG. 2 is a schematic cross section of an apparatus to be used for themanufacture of a flat permeable membrane in accordance with the presentinvention,

FIGS. 3 through 17 are electron photomicrographs showing textures offlat permeable membranes according with the present invention,

FIGS. 18 and 19 are electron photomicrographs showing textures ofcommercially available porous membranes, and

FIGS. 20 through 22 are electron photomicrographs showing textures offlat permeable membranes not incorporating a blood plasma seed formingagent.

DESCRIPTION OF PREFERRED EMBODIMENT

Now the present invention will be described more specifically below withreference to the accompanying drawings. FIG. 1 is a diagram depicting,as a model, the cross section of a flat permeable membrane accordingwith the present invention. As noted from the diagram, this is a flatpolyolefin membrane 1 having a thickness, T, in the range of 10 to 500μm, preferably 20 to 300 μm. This flat membrane 1 has on one surfaceside thereof a compact layer 2 formed of intimately bound finepolyolefin particles and possessed of fine pores. These fine pores havean average diameter in the range of 0.01 to 2 μm, preferably 0.02 to 0.5μm. This surface is flat and smooth. The flat membrane 1 has in theinterior and the other surface thereof a layer 4 of an aggregate ofnumerous fine discrete polyolefin particles 3 of an average diameter inthe range of 0.01 to 5 μm, preferably 0.02 to 1.0 μm, so adjoined as toform fine labyrinthically continuing through pores 5 and establishcommunication between the opposite surfaces of the membrane. Thethickness 7 of the aforementioned compact layer accounts for not morethan 30%, preferably for 0.1 to 5%, of the total thickness of themembrane. The compact layer 2, if present at all, is desired to have assmall a thickness as possible. In the surface of the membrane oppositethe surface constituting the compact layer 2, fine polyolefin particlesare intimately bound substantially similarly to the fine particles ofthe interior and fine pores of a relatively large diameter (such as inthe range of 0.1 to 5 μm, preferably 0.1 to 2 μm) as compared with thefine pores in the compact layer 2 are formed.

The porous membrane according with the present invention areparticularly useful for the separation of blood components. In thiscase, the membrane used for this purpose is a porous polyolefin membranehaving a thickness in the range of 10 to 500 μm and a porosity in therange of 10 to 85% and possessing through pores of an average diameterin the range of 0.01 to 5 μm, which porous polyolefin membrane ischaracterized by exhibiting shrinkage of not more than 6.0% after a heattreatment performed at 121° C. for 120 minutes. The term "membrane forseparation of blood components" as used herein means a membrane to beused for separating whole blood into blood cells and blood plasma and amembrane to be used for separating the blood plasma into high molecularweight substances and other substances. The porosity of the membranecontemplated by this invention is effective in separating the bloodplasma into high molecular weight substances and other substances. Theterm "high molecular weight substances," though not clearly defined,designates substances of molecular weights larger than the molecularweight of albumin. For example, immune globulin M (IgM; Mw about950,000), low-density lipoprotein (LDL; Mw about 1,200,000-3,300,000),immune complexes, and rheumatic factors answer the description.

The porous membrane of this invention has a thickness in the range of 10to 500 μm. If the thickness is less than 10 μm, the membrane suffersfrom insufficiency of strength and tends to sustain pinholes. If thethickness exceeds 500 μm, the membrane incorporated in a final productgives rise to a module too large to be practical. The thickness of themembrane preferably is in the range of 20 to 300 μm. Further, the porousmembrane of the present invention possesses a porosity in the range of10 to 85%. If the porosity is less than 10%, the membrane fails toacquire sufficient permeability. If the porosity exceeds 85%, themembrane suffers from insufficiency of strength and tends to sustainpinholes. Preferably, the porosity is in the range of 30 to 80%. Themethod for determination of the porosity and the formula for calculationthereof will be described afterward. The porous membrane of the presentinvention has through holes of an average diameter in the range of 0.01to 5 μm. It is because of the presence of these through holes that themembrane is capable of separating blood components. The average porediameter is variable with the substances contained in the bloodcomponents subjected to the separation with the membrane. If the averagepore diameter is less than 0.01 μm, the membrane is incapable of passingsuch useful low molecular weight substances as albumin. If this diameterexceeds 5 μm, the membrane is completely penetrated by blood cells. Whenthe porous membrane is intended for the separation of high molecularweight substances from the blood plasma, the average pore diameter isdesired to fall in the range of 0.02 to 2.0 μm.

The porous membrane of the present invention is desired to exhibitshrinkage not exceeding 6.0% after a heat treatment performed at 121° C.for 120 minutes. It is because the porous membrane possesses aconstruction as described above that this membrane exhibits theoutstanding properties as a membrane for the separation of bloodcomponents.

The expression "heat treatment performed at 121° C. for 120 minutes"implies the high-pressur steam sterilization specified by the JapanesePharmacopoeia. The term "shrinkage" as used herein means the extent ofchange of the porous membrane before and after the aforementioned heattreatment. When the porous membrane is in the form of a flat sheet, thechange in the length of the porous membrane in the axial direction ofmolding and in the length in the direction perpendicular to the axialdirection of molding after the aforementioned heat treatment is requiredto be not more than 6.0%. If the shrinkage exceeds 6.0%, the amount ofwater allowed to permeate the membrane after the heat treatment isdescribed and, therefore, the membrane provides no sufficient separationof blood components as described more fully afterward. Preferably, theshrinkage is not more than 3.0%.

The porous membrane of the present invention is made of a polyolefin. Asthe polyolefin, one member or a mixture of two or more members selectedfrom the group consisting of polyethylene, polypropylene, andethylenepropylene copolymer can be used. Among other polyolefins citedabove, polypropylene proves particularly desirable.

The flat permeable membrane of the foregoing description is prepared asfollows, for example. As illustrated in FIG. 2, a mixture 11 comprisinga polyolefin, an organic filler, and a crystal seed forming agent is fedvia a hopper 12 to a mixer such as, for example, a twin-screw extruder13, there to be melted, mixed, and extruded. Then, the extruded mixtureis forwarded to a T die 14 and discharged therethrough in the form of aflat membrane. Subsequently, the molten membrane is brought into contactwith a cooling roll 15 to be cooled and solidified. The membrane, whennecessary, is further brought into contact with another cooling roll 16and feed rolls 17, 18, stretched with drawing rolls 19, 19, and wound upon a takeup roll 20.

After the flat membrane 21 so cooled and solidified is wound up on thetakeup roll 20, it is cut into pieces of a prescribed length, thenimmersed in a liquid extractant to be deprived of the organic filler byextraction, and dried when desired. Consequently, the flat permeablemembrane is produced. Further, the flat permeable membrane is subjectedto a heat treatment under maintaining a certain or desired area toobtain the flat permeable membrane having good dimensional stability.Furthermore, shape of the side contacting with the roll is depended onthe shape of the surface of the roll, so if the surface of the roll issmooth, contact surface of the membrane becomes smooth.

The polyolefin to be used as the raw material in the present inventionmay be polypropylene or polyethylene, for example. It is desired to beof a grade having a melt index (M.I.) in the range of 5 to 70,preferably 15 to 65. In the polyolefins, polypropylene proves mostdesirable. In the various grades of polypropylene, those possessinghigher degrees of crystallization prove more desirable than thosepossessing lower degrees of crystallization. The degree ofcrystallization represents the percentage by weight of the crystallizedportion of a given polypropylene based on the total weight of thepolypropylene and it is defined by X-ray diffraction, infraredabsorption spectrum, or density. Generally, the vinyl type high polymer--CH₂ --CHR)_(n) can assume any of the three steric structures, i.e.isotactic and syndiotactic structures which have regularity and anatactic structure which has no regularity, depending on the location ofthe substitutent R. In a given polymer, the ease of crystallizationincreases in proportion as the proportion of the isotactic orsyndiotactic structure increases. This rule also applies topolypropylene. The degree of crystallization of polypropyleneproportionately increases with the proportion of the isotactic part ofthe polymer, namely, the degree of tacticity. In terms of tacticity, acriterion different from the degree of polymerization, the polypropyleneto be used in the present invention is desired to have a tacticity ofnot less than 97%.

The organic filler is required to be uniformly dispersible in thepolyolefin in a fused state and, at the same time, easily soluble in theextractant which will be described more fully afterward. Typicalexamples of the filler of the foregoing description include liquidparaffin (number-averaged molecular weight in the range of 100 to2,000), α-olefin oligomers such as ethylene oligomer (number-averagedmolecular weight in the range of 100 to 2,000), propylene oligomer(number-averaged molecular weight in the range of 100 to 2,000), andethylene-propylene oligomer (number-averaged molecular weight in therange of 100 to 2,000), paraffin waxes (number-averaged molecular weightin the range of 200 to 2,500), and various hydrocarbons. The liquidparaffin proves particularly desirable.

The amount of the organic filler to be used is desired to fall in therange of 35 to 600 parts by weight, preferably 50 to 300 parts byweight, based on 100 parts by weight of the polyolefin. If the amount ofthe organic filler is less than 35 parts by weight, the flat porousmembrane produced fails to acquire a sufficient permeability to albumin.If this amount exceeds 600 parts by weight, the mixture to be processedinto the flat membrane has too low viscosity to be extrusion molded inthe form of a membrane. The raw material is prepared (designed) by thepremixing method which comprises melting and mixing the componentsweighed out in prescribed proportions by the use of a twin-screw typeextruder, for example, extruding the resultant molten mixture, andpelletizing the extruded mixture.

The crystal seed forming agent to be incorporated in the raw material inthe present invention is an organic heat-resisting substance which has amelting point required to exceed 150° C. and desired to fall in therange of 200° to 250° C. and a gel point exceeding the temperature atwhich the polyolefin to be used begins to crystallize. The incorporationof the crystal seed forming agent in the raw material is aimed atdecreasing the polyolefin particles in diameter and controlling thediameter of the pores to be formed by the organic filler incorporated inthe raw material and subsequently removed therefrom by extraction.Typical examples of the crystal seed forming agent are1,3,2,4-dibenzylidene sorbitol,1,3,2,4-bis(p-methylbenzylidene)-sorbitol, 1,3,2,4(p-ethylbenzylidene)-sorbital, bis(4-t-butylphenyl)-sodium phosphate,sodium benzoate, adipic acid, talc, and kaolin.

Generally, the crystal seed forming agent is used for improving thetransparency of the resin to be formed.

In the present invention, owing to the use of the crystal seed formingagent, the polyolefin particles can be shrunken to an extent that thediameter of the pores formed in the membrane will not be controlled bythe diameter of the polyolefin particles and, as the result, the voidsto be formed subsequently by the removal of the organic filler byextraction can be controlled to a diameter conforming with the objectsof the membrane. The amount of the crystal seed forming agent to beincorporated in the raw material is required to fall in the range of 0.1to 5 parts by weight, preferably 0.3 to 1.0 part by weight, based on 100parts by weight of the polyolefin.

The mixture of raw materials prepared as described above is melted andmixed as with a twin-screw extruder at a temperature in the range of160° to 250° C., preferably 180° to 230° C. and discharged in the formof a flat membrane through a T die. The molten membrane so emanatingfrom the T die is allowed to fall into contact with a cooling roll to becooled and solidified. The cooling roll is kept at a prescribedtemperature by circulation therethrough of cold water or some othersuitable cooling medium. At this time, the cooling temperature (thetemperature of the cooling roll) is in the range of 10° to 100° C.,preferably 30° to 80° C. If this temperature is less than 10° C., thecooling speed is so high that the phase separation does not proceedsufficiently and the permeability of the membrane to albumin isinsufficient. If the temperature exceeds 100° C., the polyolefincrystallizes so slowly as to accelerate fusion and association ofadjacent fine particles, decrease the porosity of the membrane, andincrease the diameter of fine through pores, with the result that themembrane acquires a texture incapable of removing pathogenicmacromolecules and liable to be clogged.

The extractant to be used in this invention can be any of the substancescapable of dissolving and extracting the organic filler withoutdissolving the polyolefin forming the membrane. Typical examples of theextractant are alcohols such as methanol, ethanol, propanols, butanols,hexanols, octanols, and lauryl alcohol, and halogenated hydrocarbonssuch as, 1,1,2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane,dichlorofluoromethane, and 1,1,2,2-tetrachloro-1,2-difluoroethane. Inthe extractants cited above, halogenated hydrocarbons prove desirable interms of ability to extract the organic filler. From the standpoint ofsafety on the part of the human system, chlorofluorinated hydrocarbonsprove particularly desirable.

The porous membrane obtained as described above is subjected to a heattreatment for further stabilization of the texture and permeabilitythereof. This heat treatment is carried out in an atmosphere of such gasas air, nitrogen, or carbon dioxide at a temperature 20° to 50° C. lowerthan the melting point of the polyolefin for a period in the range of 1to 120 minutes, preferably 2 to 60 minutes. To undergo this heattreatment effectively, the porous membrane is required to be maintainedin a certain or desired area during the heat treatment. In order tomaintain the certain area, the flat membrane may be cut into pieces of aprescribed length in advance of the heat treatment. Although the heattreatment can be made even before the extraction of the organic fillerso long as the membrane of polyolefin has been cooled and solidified.

For the present invention, it is essential that the membrane should bekept from exposure to any extraneous force such as elongation throughoutthe entire course of manufacture described above. If the external forcesuch as elongation is suffered to confer persistent stress upon the webof the membrane, the intense heat applied during the sterilization in anautoclave seriously affects the texture and permeability of the membranebecause of thermal shrinkage. It is, therefore, imperative that themembrane should be kept from exposure to tension by all means even whenthe membrane already cooled and solidified is wound up on the takeuproll, for example.

The flat permeable membrane obtained as described above is a sheet of athickness in the range of 10 to 500 μm, preferably 20 to 300 μm. Asnoted clearly from FIG. 3 (roll temperature 12° C.), FIG. 4 (rolltemperature 30° C.), FIG. 5 (roll temperature 40° C.), FIG. 6 (rolltemperature 50° C.), and FIG. 7 (roll temperature 60° C.) which arephotographs taken through a scanning electron microscope at 3,000magnifications (applicable hereinafter), the membrane assumes a texturewhich has in the surface of the side exposed to the roll a compact layerformed of intimately bound fine polyolefin particles and possessed offine pores. In the surface of the side exposed to the air opposite theroll, the texture has a layer formed of intimately bound fine polyolefinparticles and possessed of fine pores of a relatively large diametercompared with the pores in the aforementioned compact layer as clearlynoted from FIG. 8 (roll temperature 12° C.), FIG. 9 (roll temperature30° C.), FIG. 10 (roll temperature 40° C.), FIG. 11 (roll temperature50° C.), and FIG. 12 (roll temperature 60° C.). In the interior, thetexture has a layer formed of an aggregate of relatively large discretepolyolefin particles so adjoined that their interstices formlabyrinthically continuing through pores as clearly noted from FIG. 13(roll temperature 12° C.), FIG. 14 (roll temperature 30° C.), FIG. 15(roll temperature 40° C.), FIG. 16 (roll temperature 50° C.), and FIG.17 (roll temperature 60° C.). In the case of the membrane producedwithout incorporation of the crystal seed forming agent, the surface ofthe texture exposed to the roll (roll temperature 50° C.) is as shown inFIG. 20 and the cross section of the texture in FIG. 21, and the surfaceexposed to the air in FIG. 22 respectively.

It is believed that the membrane produced by the method of thisinvention acquires such an anisotropic texture as described abovepossibly for the following reason.

The polyolefin admixed with the organic filler and the crystal seedforming agent is extruded in the form of a sheet and the extruded sheetis brought into contact with the cooling roll. Thus, the solidificationof the extruded sheet of polyolefin begins in the surface of the sheetexposed to the roll. Since the cooling of the interior and the surfacenot exposed to the roll is retarded as compared with the surface exposedto the roll, phase separation between the polyolefin and the organicfiller in the membrane proceeds in proportion to the delay in thecooling, with the result that the organic filler which has beendispersed is agglomerated to some extent. It is surmised that, as theresult of this peculiar phenomenon, the permeable membrane of thepresent invention acquires a special texture containing small pores inthe surface exposed to the roll and large pores in the interior and thesurface not exposed to the roll. Further, in the surface of the membraneexposed to the roll, the force generated in consequence of the contactof the membrane with the roll crushes the polyolefin particles and addsto the conspicuousness of difference in texture between the surfaceexposed to the roll and the other parts of the membrane.

Since the solidification of the extruded sheet of polyolefin begins inthe surface of the sheet exposed to the roll as described above, thedelay in this solidification increases in proportion as the distancefrom the surface exposed to the roll increases. This is why the poresare larger in diameter in the surface of the membrane not exposed to theroll than the pores in the interior of the membrane. Probably because ofthe mechanism described above, the pores in the permeable membrane ofthis invention gradually increase in diameter from the surface exposedto the roll toward the surface not exposed to the roll.

As noted from the diagram, the porosity and the diameter of pores areboth decreased and the pores assume a circular cross section in thesurface exposed to the roll when the temperature of the cooling roll islow (enough to effect sudden cooling). When the temperature of the rollis elevated to 50° to 60° C., the porosity is improved and the pores areenabled to communicate with one another. To be specific, when thecooling speed is heightened, the liquid paraffin assumes a dispersedphase in the surface texture of the membrane. This dispersed phase ofliquid paraffin can be approximated to a continuous phase by loweringthe cooling speed. When the cooling speed is excessively lowered,however, the phase separation is accelerated and the association ofadjacent polyolefin particles is promoted and, as the result, the numberof pores is conversely decreased. Since the liquid paraffin phase isdestined to form fine pores after extraction thereof, the liquidparaffin is desired to be in a continuous phase. From the standpoint ofstrength, the polyolefin which constitutes itself the matrix of themembrane is desired to be similarly in a continuous phase. It isimportant that the membrane should be formed under conditions whichpermit the polyolefin and the liquid paraffin to be separated from eachother, each forming a continuous phase. These conditions are attained inthe aforementioned range of temperature.

The permeable membrane so produced has a porosity in the range of 10 to85%, preferably 30 to 60%.

The conventional flat polyolefin membrane produced by the stretchingmethod is devoid of particles as clearly noted from the cross sectionthereof illustrated in FIG. 18 and the surface illustrated in FIG. 19.It is instead allowed to form fine pores with cracks which occur whenthe membrane is stretched.

In the present invention, the side of the permeable membrane exposed tothe roll is enabled to acquire a flat smooth surface so long as the rollto be used has a flat smooth surface. When the blood plasma is passed onthe flat smooth surface of the membrane, it forms a uniform flow freefrom turbulence because the surface has no irregularities. The flatsmooth surface does not easily cause clogging. It also provesadvantageous in fractionating property and treating capacity.

The term "porosity" as used in the specification is defined and themethod for its determination is indicated below. The definition of theterm "average particle diameter" and the method for its determinationare both indicated below.

1. Method for determination and definition of porosity

A given sample of flat membrane is immersed in ethanol. Then the ethanolis displaced with water to impregnate the membrane with water. Theimpregnated membrane is weighed (Wwet). Let Wdry stand for the weight ofthe membrane in its dry state and ρ for the density of polymer in g/ml,and the porosity will be calculated by the following formula. ##EQU1##

2. Method for determination of average particle diameter

With the aid of a scanning electron microscope (Model JSM-50A orJSM-840, made by Japan Electron Optics Laboratory Co., Ltd.), 50 fineparticles of a given sample viewed at 10,000 or 3,000 magnifications aremeasured in diameter and the 50 numerical values so found are averaged.

3. Method for determination of average pore diameter

With the aid of the scanning electron microscope, 100 pores of a givensample viewed at 10,000 (or 20,000) magnifications are measured indiameter and the 100 numerical values so found are averaged.

Now, the present invention will be described more specifically belowwith reference to working examples. Examples 1-3

In a twin-screw extruder (produced by Ikegai Iron Works, Ltd. andmarketed under trademark designation of "PCM-30-25"), 100 parts byweight of polypropylene having a M.I. of 23, 100 parts by weight ofliquid paraffin (number average molecular weight 324), and a varyingamount, indicated in Table 1, of 1,3,2,4-dibenzylidene sorbitol(produced by E.C. Co. and marketed under trademark designation of"EC-1") or 1,3,2,4-bis(p-methylbenzylidene)-sorbitol (product byShin-Nippon Rika K.K. and marketed under trademark designation of "GelolMD") as a crystal seed forming agent were melted and mixed and extruded.

The extruded mixture was then pelletized. In an apparatus constructed asillustrated in FIG. 2, the pellets were melted with a twin-screwextruder (produced by Ikegai Iron Works, Ltd. and marketed undertrademark designation of "PCM-30-25") at 150° to 200° C. and the moltenmixture was discharged through a T die 14 having a width of 0.6 mm intothe ambient air at a rate of 70 g/min. The discharged molten mixture wasallowed to fall into contact with the water on the surface of a coolingroll 15 disposed below the T die 14 to be cooled and solidified. Thesolidified web was stretched with a stretching rolls 19 and 19 and thenwound up on a takeup roll 20. The sheet so wound up on the takeup roll20 was cut into pieces of a prescribed length and immersed twice in1,1,2-trichloro-1,2,2-trifluoroethane (hereinafter referred to as "Freon113") at 25° C. for 10 minutes to effect extraction of a fixed duration.The sheet was then heated in air at 130° C. for two minutes and treatedwith an aqueous 50% ethanol solution to be rendered hydrophilic.Consequently, there was obtained a flat permeable membrane exhibitingproperties as shown in Table 1.

CONTROLS 1 AND 2

Commercially available flat permeable polypropylene membrane and flatpermeable polytetrafluoroethylene membrane both produced by thestretching method were subjected to the same test as in Example 1. Theresults are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________                          Blue dextran                 Blue                       Crystal seed          test     Water         Thick-                                                                              dextran                    forming agent    Roll Perme-                                                                            Flux flux (ml/     ness of                                                                             flux                                  Amount                                                                              Tempera-                                                                           ability                                                                           (ml/hr)                                                                            min · mmHg ·                                                         Porosity                                                                           membrane                                                                            Water flux                 Example                                                                            Type  (phr) ture (°C.)                                                                  (%) (A)  m.sup.2) (B)                                                                           (%)  (μm)                                                                             (A/B)                      __________________________________________________________________________    1    EC-1  0.5   50   0   11.9 1.2      36   130   9.9                        2    EC-1  1.0   50   0   10.1 0.9      37   130   12.1                       3    Gelol MD                                                                            0.3   50   0   11.6 1.3      37   130   8.9                        Control 1                                                                          --    --    --   0   9.4  5.0      40   30    1.9                        Control 2                                                                          --    --    --   0   3.3  0.46     20   80    7.2                        __________________________________________________________________________

The blue dextran test mentioned in Table 1 was carried out as follows.An aqueous solution of 0.05% by weight of Blue Dextran 200 (product ofFarmarcia Corp, having weight average molecular weight of 2,000,000) wascaused to penetrate a given sample under pressure of 0.3 kg/cm² todetermine permeability of the sample and the amount of the aqueoussolution (flux) passed through the sample during the first one hour. Theporosity, P, was calculated in accordance with the following formula.##EQU2## (wherein W stands for weight of water contained and D forabsolute dry weight).

The amount of water passed was determined by causing water to penetratethrough a sample membrane 1.38×10⁻³ m² in area under pressure of 150mmHg, clocking the time required for a fixed volume (5 ml) of water topass through the sample, and reporting the time.

The secondary filter to be used in the plasma separator is desired toexhibit permeability as close to 0 as possible in the blue dextran testand to possess as high a flux as possible. The ratio of blue dextranflux/water flux increases with the decreasing extent of clogging causedin the membrane by the solute. Thus, the ratio is desired to be as highas possible.

The performance of the membrane is rated in terms of the factors coupledwith the results of rating with bovine blood plasma which will bedescribed fully afterward. Modules of a membrane area of 100 cm² (5×20cm) were prepared by using permeable membranes obtained in Examples 1and 3 and Controls 1 and 2. A given module was immersed in a constanttemperature bath kept at 37° C. The bovine blood plasma (containing 5.1of albumin and 9.4 g of total protein per liter) obtained with the firstfilter of a plasma separator made by Terumo Co., Ltd. was fed through anair chamber to the module with a pump I at a rate of 0.2 ml/min. (bloodplasma flow rate 280 cm/min), with the filtrate circulated at a rate of70 ml/min. to the air chamber with a pump II. The residue of filtrationwas assayed by HPLC (column TSK-G3000SW, flow rate 1 ml/min, solvent0.3M-Nacl-containing 0.1M Soren Buffer (pH 7.0), detection 280 nm O.D.).The results were shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                   Recovery ratio (%).sup. (2)                                                                   A/M                                                Peremeable                                                                            Δp.sup.(1)  Glob- Macro- enhance-.sup.(3)                       membrane                                                                              (mm Hg)  Albumin  ulin  molecule                                                                             ment (%)                               ______________________________________                                        Example 1                                                                             21       84.9     64.7  16.1   427                                    Example 3                                                                             43       80.4     60.6  13.1   514                                    Control 1                                                                             89       74.9     60.3  19.4   287                                    Control 2                                                                             102      38.0     26.7  10.2   372                                    ______________________________________                                         .sup.(1) ΔP = P.sub.Qf = 50 - P.sub.Qf = 10                             .sup.(2) Average of the values up to Qf = 50 (ml).                            .sup.(3) [(A/M of filtrate)/(A/M of blood plasma)1] × 100 (%).     

EXAMPLES 4-8

Flat permeable membranes were obtained by following the procedure ofExample 1 by using 100 parts by weight of polypropylene having a M.I. of30, 100 parts, 150 parts, and 174 parts respectively by weight of liquidparaffin (number average molecular weight of 324), and 0.5 parts byweight of EC-1. They were tested by following the procedure ofExample 1. The results were shown in Table 3.

The membranes of Examples 4-8 and Controls 1 and 2 were tested withbovine blood plasma by following the procedure of Example 1. The resultswere shown in Table 4.

                                      TABLE 3                                     __________________________________________________________________________     Example                                                                            (parts by weight)Liquid paraffin content                                                  (°C.)temperatureRoll                                                          (μm)thicknessMembrane                                                            (%)hr)(A)PermeabilityFlux(ml/Blue dextran                                    test         (ml/min · mmHg                                                      · m.sup.2)Water                                                                  (%)Porosity                                                                        ##STR1##           __________________________________________________________________________    4    100         50     165   0      9.1  1.70       38.8 5.4                 5    100         60     165   0      9.3  1.80       39.0 5.2                 6    100         70     165   0      10.5 2.10       40.1 5.0                 7    150         45      45   0.2    11.0 6.81       39.5 1.6                 8    174         40      45   0      12.3 6.51       43.8 1.9                 __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    Permeable                                                                           Δp                                                                           Recovery ratio (%)                                                                              Enhancement (%)                                                                        Permeability (%)                        membrane                                                                            (mmHg)                                                                             Albumin                                                                            Globulin                                                                           Macromolecule                                                                         A/G A/M  Albumin                                                                            Globulin                                                                           Macromolecule                 __________________________________________________________________________    Control 1                                                                           89   74.9 60.3 19.4    24.1                                                                              287  65.5 48.5 12.8                          Control 2                                                                           102  38.0 26.7 10.2    42.3                                                                              372  30.4 19.7 6.8                           Example 4                                                                           47   79.4 51.8 7.7     53.2                                                                              931  74.0 41.4 5.1                           Example 5                                                                           18   88.8 70.6 20.3    25.9                                                                              341  85.1 58.6 12.9                          Example 6                                                                           14   88.7 64.6 17.9    37.4                                                                              397  85.2 54.4 12.2                          Example 7                                                                           9    90.6 68.4 14.2    32.5                                                                              538  88.3 57.4 10.2                          Example 8                                                                           9    91.6 66.8 14.0    37.1                                                                              554  89.0 57.4 9.8                           __________________________________________________________________________

EXAMPLE 9

In a twin-screw extruder (produced by Ikegai Iron Works, Ltd. andmarketed under trademark designation of "PCM-30"), 100 parts by weightof polypropylene having a M. I. of 30, 130 parts by weight of liquidparaffin (number average molecular weight of 324), and 0.3 part byweight of 1,3,2,4-bis(para-ethylbenzylidene)-sorbitol as a crystal seedforming agent were melted, mixed, and extruded. The extruded mixture waspelletized. The pellets were melted in the same extruder at 150° to 200°C. and the molten mixture was extruded through a T die having a slitwith of 0.6 mm at a rate of 100 g/min into the ambient air. The extrudedmolten mixture was allowed to fall into contact with a cooling rollhaving a surface temperature of 35° C. to be cooled and solidified. Thecooled sheet was wound up on a takeup roll. The sheet so wound up wascut into pieces of a prescribed length. A membrane so obtained was fixedin the longitudinal and lateral directions, immersed twice in1,1,2-trichloro- 1,2,2-trifluoroethane at 25° C. for 10 minutes toeffect extraction of liquid paraffin, and then heated in air at 135° C.for two minutes. The membrane so produced was tested for the propertiesdescribed above. The results are shown in Table 1. The sample ofmembrane used for evaluation of permeability was treated with an aqueous50% ethanol solution to be rendered hydrophilic and then washed withwater before use.

EXAMPLE 10

A porous membrane was obtained by following the procedure of Example 9,except that the amount of liquid paraffin was changed to 170 parts byweight. The properties of the membrane consequently produced are shownin Table 5.

CONTROL 3

A porous membrane was obtained by following the procedure of Example 10,except that the fixing of the sheet into pieces of a prescribed lengthand the heat treatment were omitted. The properties of the membraneconsequently obtained are shown in Table 5.

CONTROL 4

A commercially available permeable polypropylene membrane produced bythe stretching method (produced by Polyplastic Co., Ltd. and marketedunder trademark designation of "Dulagart 2500") was tested forproperties by following the procedure of Example 9. The results areshown in Table 5.

EXAMPLE 11

A porous membrane was obtained by following the procedure of Example 9,except that the temperature of the heat treatment was changed to 117° C.The membrane consequently obtained was tested for properties. Theresults are shown in Table 5.

EXAMPLE 12

A porous membrane was obtained by following the procedure of Example 10,except that the temperature of the heat treatment was changed to 120° C.The properties of the membrane consequently obtained are shown in Table5.

CONTROL 5

A porous membrane was obtained by following the procedure of Example 9,except that the temperature of the heat treatment was changed to 100° C.The properties of the membrane consequently produced are shown in Table5.

                                      TABLE 5                                     __________________________________________________________________________    Shrinkage of membrane                                                         before and after                                                              autoclave sterilization        Change in average                                                                         Water flux                         (121° C., 120 minutes)                                                                    Change in porosity                                                                        pore diameter                                                                             (ml/hr · mmHg                                                        · m.sup.2)                            Perpendicular                                                                        Before                                                                              After Before                                                                              After Before                                                                             After                         Axial       to axial                                                                             autoclave                                                                           autoclave                                                                           autoclave                                                                           autoclave                                                                           autoclave                                                                          autoclave                     direction   direction of                                                                         steril-                                                                             steril-                                                                             steril-                                                                             steril-                                                                             steril-                                                                            steril-                       of forming  forming                                                                              ization (%)                                                                         ization (%)                                                                         ization (%)                                                                         ization (%)                                                                         ization                                                                            ization                       __________________________________________________________________________    Example 9                                                                           0     0      40.6  40.1  0.20  0.20  330  333                           Example 10                                                                          0     0      42.1  41.9  0.25  0.25  610  607                           Control 3                                                                           14.1  14.1   42.5  21.4  0.25  0.20  610  205                           Control 4                                                                           19.9  7.1    46.3  36.5  0.22  0.26  360  430                           Example 11                                                                          5.6   2.3    40.3  39.5  0.19  0.18  335  329                           Example 12                                                                          2.7   2.6    43.3  42.8  0.26  0.25  618  610                           Control 5                                                                           10.4  5.4    40.5  30.8  0.20  0.16  328  159                           __________________________________________________________________________

It is noted from the foregoing results that the porous membranesaccording with this invention thermally stable to defy dimensionalchange by the heat of autoclave sterilization and avoid change inporosity, average pore diameter, and amount of water passed, whereas themembranes of controls were notably shrunken after autoclavesterilization so that, when incorporated in products, they had thepossibility of sustaining rupture of sealed parts and entailing otherdrawbacks after the autoclave sterilization. These membranes were alsodegraded seriously in other properties. Probably because the porousmembranes produced by the stretching method sustained persistent innerstress due to the external force of stretching applied during themolding and the stress remained after the molding, the porous membranesyielded to dimensional change on exposure to heat.

The physical properties involved in Example 8 and the following exampleswere determined as follows.

(1) Thermal shrinkage:

A disc of a given membrane 156 mm in diameter was immersed in ethanoland then treated with water for displacement of the ethanol with water.The disc impregnated with water was placed in an autoclave and heatedtherein at 121° C. for 120 minutes. The length of the membrane afterthis heat treatment was compared with the length before the heattreatment to fine the decrease in percentage. This shrinkage wasreported.

(2) Thickness of membrane:

This dimension was actually measured by the use of a micrometer.

(3) Porosity (P):

A given flat porous membrane was immersed in ethanol and treated withwater for displacement of ethanol with water. The membrane soimpregnated with water was weighed (W_(w)). The membrane, in a drystate, was weighed (W_(D)). The porosity (P) was calculated by thefollowing formula: ##EQU3## wherein ρ stands for the density of thepolymer in g/ml.

(4) Average pore diameter (d):

A given sample was photographed through a scanning electron microscope(produced by Japan Electron Optics Laboratory Co., Ltd. and marketedunder trademark designation of "JSM-50A" or "JSM-840") at 10,000magnifications and 100 pores found in the photograph were measured formajor diameter (d_(A)) and minor diameter (d_(B)) to claculate theiraverage as follows. ##EQU4##

(5) Water flux:

Through a given membrane having an area of 1.38×10⁻³ m², water wascaused to pass under pressure of 150 mmHg at 25° C. The time for 5 ml ofwater to pass through the membrane was clocked.

As described above, this invention is directed to a flat permeablepolyolefin membrane 10 to 500 μm in thickness, which has in one surfacethereof a compact layer formed of intimately bound fine polyolefinparticles and possessed of fine pores and in the interior and the othersurface thereof a layer formed of an aggregate of fine discretepolyolefin particles of an average diameter in the range of 0.01 to 5 μmso adjoined as to form fine labyrinthically continuing through pores andwhich, therefore, establishes communication between the oppositesurfaces of the membranes. The aforementioned fine through pores are notlinearly passed through the membrane in the direction of thickness ofthe membrane but are formed between the aforementioned fine particles asdirected from the surface through the interior to the other surface ofthe membrane as interconnected to one another. Further, the poresoutside the compact layer are larger in diameter than the pores insidethe compact layer. When the permeable membrane is used for theseparation of blood plasma, therefore, it permits efficient removal ofpathogenic macromolecules without entailing clogging or pressure lossand provides recovery of albumin at a high ratio and fulfils itsfunction stably for a long time. The membrane, therefore, proves highlyuseful for the separation of blood plasma, especially as a secondaryfilter for the separation of blood plasma.

This invention is also directed to a method for the manufacture of aflat permeable membrane, characterized by the steps of mixing apolyolefin, an organic filler uniformly dispersible in the polyolefin inthe molten state thereof and easily soluble in an extractant to be used,and a crystal seed forming agent, discharging the resultant mixture inthe molten state thereof through a die, bringing one surface of thedischarged molten membrane into contact with a cooling roll therebycooling and solidifying the membrane, and placing the cooled andsolidified flat membrane into contact with an extractant incapable ofdissolving the polyolefin thereby extracting and removing the organicfiller from the web of the membrane. While the mixture prepared byuniform dispersion in a molten state is cooled and solidified, thepolyolefin and the organic filler in the mixture undergo phaseseparation and the organic filler is extracted from the mixture to giverise to fine pores in the interstices of the fine polyolefin particles.Further, the inclusion of the crystal seed forming agent promotes sizereduction of the particles of polyolefin. Thus, the diameter of the finepores can be regulated as desired. Moreover, the phase separation can beregulated in the direction of the thickness of the membrane by suitablyselecting the amount of the organic filler to be incorporated, theamount of the crystal seed forming agent to be incorporated, and thecooling temperature, for example.

While stretching method is incapable of producing a membrane in athickness exceeding about 40 μm, this invention is capable of producinga membrane in a greater thickness. The membrane produced in accordancewith its invention, therefore, enjoys improvement in strength andpermits effective use in a greater surface area. It proves useful as afilter for separation and as a substrate for coating.

What is claimed is:
 1. A method for the manufacture of flat permeable membrane, comprising the steps of:mixing a polyolefin, an organic filler uniformly dispersible in said polyolefin in the molten state thereof, and crystal seed forming agent for said polyolefin; discharging the resultant mixture in the molten state thereof through a die; bringing one surface of the discharged molten membrane into contact with a cooling roll thereby cooling and solidifying said membrane; placing the cooled and solidified flat membrane into contact with an extractant capable of dissolving and extracting said organic filler and incapable of dissolving said polyolefin thereby extracting and removing said organic filler from said membrane; and subjecting the cooled and solidified flat membrane in a fixed state in longitudinal and lateral directions to a heat treatment at a temperature 20° to 50° C. lower than the melting point of said polyolefin.
 2. A method according to claim 1, wherein said organic filler is a hydrocarbon having a boiling point exceeding the melting point of said polyolefin.
 3. A method according to claim 2, wherein said hydrocarbon is fluid paraffin or an α-olefin oligomer.
 4. A method according to claim 1, wherein said organic filler is incorporated in an amount in the range of 35 to 600 parts by weight based on 100 parts by weight of said polyolefin.
 5. A method according to claim 1, wherein said polyolefin is at least one member selected from the group consisting of polyethylene, polypropylene, and ethylenepropylene copolymer.
 6. A method according to claim 1, wherein said crystal seed forming agent is an organic heat-resisting substance having a melting point of not less than 150° C. and a gel point exceeding the temperature at which said polyolefin begins to crystallize.
 7. A method according to claim 1, wherein said crystal seed forming agent is incorporated in an amount in the range of 0.1 to 5 parts by weight based on 100 parts by weight of said polyolefin.
 8. A method according to claim 1, wherein said extractant is at least one member selected from the group consisting of alcohols and halogenated hydrocarbons.
 9. A method according to claim 1, wherein said temperature of said cooling roll is in the range of 10° to 100° C.
 10. A method according to claim 1 wherein said heat treatment subjecting step reduces shrinkage of said membrane after heat treatment performed at 121° C. for 120 minutes to less than 6%.
 11. A method according to claim 1 wherein said heat treatment subjecting step reduces shrinkage of said membrane after heat treatment performed at 121° C. for 120 minutes to less than 3%.
 12. A method according to claim 1 wherein said subjecting step is carried out after said placing step.
 13. A method according to claim 1 wherein the extractant is a chlorofluorinated hydrocarbon.
 14. A method for the manufacture of a flat permeable membrane having a thickness of 10 to 500 μm and having in one surface thereof as a filtering surface a compact layer formed of intimately bound fine polyolefin particles and possessed of fine pores and in the interior and other surface thereof a layer formed on an aggregate of fine discrete polyolefin particles of an average diameter in the range of 0.01 to 5 μm so adjoined as to form fine labyrinthically continuing through pores and which, therefore, establish communication between the opposite surfaces of said membrane, said membrane having a shrinkage of not more than 6% after a heat treatment performed at 121° C. for 120 minutes said method comprising the steps of:mixing 100 parts by weight polyolefin having a melt index in the range of 5 to 70 and a tacticity of not less than 97%, 35 to 600 parts by weight organic filler dispersible in said polyolefin in the molten state, and 0.1 to 5 parts by weight crystal seed forming agent; extruding the resultant mixture in the molten state through a die at a temperature in the range of 160° to 250° C.; bringing one surface of the excluded molten membrane into contact with a cooling roll kept at 10° to 100° C. thereby cooling and solidifying said membrane; placing the cooled and solidified flat membrane into contact with an extractant incapable of dissolving said polyolefin thereby extracting and removing said organic filler from said membrane; and subjecting the cooled and solidified flat membrane in a fixed state in longitudinal and lateral directions to a heat treatment at a temperature of 20° to 50° C. lower than the melting point of the polyolefin.
 15. A method according to claim 14 wherein the extractant is a chlorofluorinated hydrocarbon.
 16. A method according to claim 14 wherein said subjecting step is carried out after said placing step. 